When humans, animals, birds or fish are infected by viruses, interferon is induced. The interferon system represents the most potent biological mechanism for the control of virus replication, and the only one to prevent cell-killing by otherwise lethal viruses. The induction and production of interferon is exquisitely regulated. A single virus particle may induce the interferon genes to full production. Another kind of virus particle may suppress interferon induction. In the longterm this research is designed to understand how viral double-stranded RNA functions as the proximal inducer of interferon, what regulates the induction/production process, and how, in turn, the interferon system acts to prevent the lethal action of a virus and regulate host cell survival and virus replication during persistent infection. Specific aims include: (1) The study of interferon induction by viruses, by (i) establishing, in situ, double-stranded RNA as the proximal interferon inducer, (ii) studying the regulation of interferon yield by different viruses, (iii) defining the interferon inducer molecule for adenovirus, and (iv) developing a model for defining interferon induction dose. (2) To study the mode of action of virus particles that suppress interferon induction, (3) To test an hypothesis that silent mutations are responsible for converting viruses from non-inducers to inducers of interferon, (4) To study the involvement of prostaglandins and leukotrienes in the development of interferon inducibility, (5) To characterize a novel acid-labile chicken interferon, (6) To study a double-stranded RNA inducible double-stranded ribonuclease discovered in aged chick embryo cells, (7) To genetically clone 3'-transcribing defective-interfering particles of vesicular stomatitis virus using a single-cell procedure, (8) To develop an "absolute" test for genetic complementation between temperature-sensitive viral mutants, (9) To determine how viruses kill cells, and (10) To test further the role of the interferon system in persistent infection. To accomplish these goals we will continue to exploit a cell system that is hyperresponsive to the induction process (aged primary chick embryo cells), and a viral inducer for which one molecule of double-stranded RNA represents the threshold for interferon induction (the [+-]RNA DI-011 particle of vesicular stomatitis virus).